Pre-operational Reviews of Manufacturing Facilities

PURPOSE

To provide field guidance when responding to requests from industry for reviewing plans for construction of new or modifications of facilities prior to commercial production.

NOTE

This FMD should not be confused with and does not replace any existing pre-operational inspection and review activities such as under the Interstate Travel Sanitation, Retail Food Protection and Interstate Milk Sanitation Programs of the Center for Food Safety and Applied Nutrition; the NDA and ANDA of the Center for Drug Evaluation and Research; the licensing inspections of the Center for Biologics Evaluation and Research; and Premarket Approval inspections of the Center for Devices and Radiological Health. All of these or any other Compliance Program activities remain as directed.

BACKGROUND

District offices and other units of FDA are often asked by firms to provide comments about construction plans for new plants or major modification of an existing one as well as being present during certain construction phases. FMD 135 has been developed to provide uniform guidance in conducting these reviews.

POLICY

Providing review and comment is desirable because it may reveal defects early and prevent costly construction errors which could lead to defective operations and products. It also affords FDA the opportunity to become aware of future work load obligations and, in some cases, new technologies. Early field involvement with new or modified facilities will increase efficiency and result in the timely processing of applications.

However, it shall continue to be the manufacturer's responsibility to design, construct, qualify/validate, and operate a plant in the proper manner. The purpose for FDA reviews is to offer the best opinion as to whether or not the new or modified facilities and processing procedures would comply with current good manufacturing practice regulations (CGMPs). Any written or oral report by an FDA representative to the firm should state that the pre-operational review reflects the best opinion at that time on compliance with CGMPs.

In accepting requests for reviews, districts must ensure that it serves the objectives of FDA's overall compliance and regulatory policies. Careful control and coordination are necessary to afford timely reviews and to prevent excessive time expenditures in comparison to potential benefits. A favorable in-compliance regulatory status must exist along with the intent to manufacture for the US market prior to a firm being considered for pre-operational review.

ORA Headquarters units and the Centers which receive referrals from districts or requests for review directly from firms should coordinate any follow-up with the appropriate district, providing copies of related communications. Districts are expected to keep the appropriate Center advised of contacts with firms. ORA Headquarters units and the Centers are also expected to notify districts of meetings with firms at headquarters in sufficient time to allow attendance by a district representative. Districts are encouraged to attend the meetings. Written comments to firms should represent a consolidated response from all involved FDA units.

Reviews involving foreign facilities will be coordinated by the ORA Division of Field Investigations International Operations Branch, HFC-130, and/or the appropriate Center. However, due to costs involved, on-site pre-operational reviews of foreign facilities may not be feasible. Foreign firms may be requested to submit plans to FDA for review. Discussions with firms may be handled through conference calls or other means of communications.

TYPES OF REVIEW

Requests for review will typically occur at any one or all of the following stages:

Design Review

A design review usually involves review of conceptual drawings, proposed plant layouts, and flow diagrams for the entire facility including critical systems and areas. Such reviews provide an opportunity to emphasize the importance of the fundamental principles of good design as outlined in the CGMPs. As a result, extensive changes in design can be made with little cost and very minor delay to the design and construction cycle. A firm requesting review should be told that FDA expects the firm to prepare complete final plans and to identify, if possible, specific questions regarding how the plant will meet CGMPs or areas where FDA's comments are specifically desired. Firms should be discouraged from presenting incomplete plans or rough drafts. When the review includes a meeting with the firm, advance delivery of the package of documents to the District Office is recommended.

Pre-construction Review

Pre-construction review involves a study of the plan, elevation, and isometric drawings for all manufacturing areas and utility and process systems for the plant; i.e., drainage and water systems; product systems; compressed air systems; heating ventilation and air-conditioning (HVAC) systems; and all equipment, layouts and piping in the manufacturing and laboratory areas. Further examples, where applicable, include zones of positive air pressure; HEPA filtration and laminar flow; air locks; protective clothing; change rooms; toilet and wash-up facilities; pedestrian traffic patterns; raw materials and components, and similar considerations.

The various packages of prints, specifications, design standards, and vendors’ descriptions should be supplied in advance to permit meaningful review and comment prior to any meeting.

Construction/Equipment Installation and Qualification Review

Firms may request FDA on-site review of specific portions of the plant while construction is in progress. This would be an excellent opportunity to review piping systems and methods of construction before they are concealed by walls, floors, and ceilings. These reviews or site visits may be done in phases. Districts may exercise flexibility in the depth and frequency of attention. For instance, it may be more efficient to cover installation and qualification of equipment prior to initial production runs. The final inspectional review of validation and control data from production runs can then be accomplished quickly and more efficiently.

Pre-Production Review

At the pre-production stage, the review will normally be an inspection and should follow the guidance in the applicable Compliance Program and the IOM.

Additionally, firms may request investigators to visit new buildings or production areas during inspections on the same campus. As time permits, investigators can accommodate such requests. However, this should not be done during inspections when an official action indicated (OAI) situation exists or for firms that have an unacceptable compliance history.

Investigators conducting the review should provide the firm with general feedback and can provide firms with examples of what they have seen at similar firms. However, Investigators are not consultants and care should be taken to ensure that Investigators are providing feedback and not recommendations requiring capital expenditures that may be cGMP liabilities.

DOCUMENTATION

All pre-operational reviews should be documented in the firm’s establishment files as a Preoperational memo. Documentation should include the address of the site, the date(s) of the site review, a general description of the facility plans or modifications reviewed, and a summary of the feedback provided to the firm.

HEADQUARTERS ASSISTANCE

Support and consultation can be obtained by contacting appropriate headquarters units as follows:

Center for Drug Evaluation and Research Office of Compliance/Division of Manufacturing and Product Quality (HFD-320) (301)796-3120 FAX: (301)847-8742

Center for Biologics Evaluation and Research Office of Compliance and Biologics Quality/Division of Inspections and Survewillance (HFM-650) (301)827-6350

Office of Regional Operations Division of Field Investigations (HFC-130)* (301)827-2190

*Division of Field Investigations can provide technical and administrative assistance for inspections or on-site reviews, meetings at the district office, or to act as a representative of the district in meetings at headquarters units or in review of documents at Headquarters.